The major objective of this Academic Research Enhancement Award (AREA) R15 proposal is to evaluate the role of MUC1 protein, a member of the mucin family, in resistance of pancreatic cancer cells to oncolytic viruses (OV). About 95% of pancreas cancers are PDAs which are highly invasive with aggressive local growth and rapid metastases. Several cancer therapies proven successful in other tumor types have had little effect in treating PDA, which has a 5 year survival rate of 8-20%. Therefore there is a grea need for developing new treatment strategies for patients suffering from PDA. OV therapy is a new anticancer approach that utilizes replication-competent viruses specifically killing tumor cells. Following numerous successful preclinical studies, several OVs have now entered or are entering phase III clinical trials against various cancers, and therefore, the approval of the firs OV in North America is expected in the near future. Despite all these successes, it has become clear that several important barriers remain in the development of effective OV therapy. Several recent studies indicated that many cancer types are highly heterogeneous in their susceptibility/resistance to OVs. Mechanisms of resistance are poorly understood. Our preliminary data suggest that the resistance to virotherapy in at least some PDA cells could be due to the over-expression of MUC1 protein. MUC1 is developmentally regulated and aberrantly over expressed in many human adenocarcinomas including those of the pancreas, breast, and ovaries. We hypothesize that over-expression of MUC1 plays an important role in the resistance of PDA cell lines to OV therapy. In Aim 1 we will examine this hypothesis using several genetic and biochemical approaches in vitro, while in Aim 2 we will address this problem in nude athymic mice and in an immunocompetent model of PDA. As MUC1 is already used as a prognostic and diagnostic marker for PDA, understanding the role of MUC1 in resistance of pancreatic cancers to OV therapy is very important not only for better understanding virus-host interactions in cancer cells, but for potential practical implications for prescreening of cancer patients for a particular OV therapy. PUBLIC HEALTH RELEVANCE: This Academic Research Enhancement Award (AREA) R15 proposal is aimed at understanding the role of MUC1 protein in resistance of pancreatic cancer cells to oncolytic virotherapy. About 95% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDA) which are highly invasive with aggressive local growth and rapid metastases to surrounding tissues. PDA is considered one of the most lethal abdominal malignancies and the development of new rational treatment strategies for patients suffering from PDA is of utmost importance. Our preliminary data suggest that the resistance to virotherapy in at least some PDA cells is due to the over-expression of MUC-1 protein, a member of the mucin family. We will examine this hypothesis using several genetic and biochemical approaches in vitro and in vivo. As MUC1 is already used as a prognostic and diagnostic marker for PDA, understanding the role of MUC1 in resistance to oncolytic virotherapy is very important not only for better understanding virus-host interactions in cancer cells, but for potential practical implications for prescreening of cancer patients for a particula oncolytic therapy.